The most well-known anthracycline anticancer drugs are doxorubicin and daunorubicin, which contain a 13-keto group and a 5-keto group. Doxorubicin, disclosed in U.S. Pat. No. 3,590,028, has a wide spectrum of anticancer utility and is used in the treatment of leukemias, lymphomas, and solid tumors. Daunorubicin, disclosed in U.S. Pat. No. 3,616,242, is useful in the treatment of acute leukemias. However, the utility of these drugs is limited by a serious side effect of cardiotoxicity so that the total amount of drug that can be given to a patient cannot exceed 550 mg/M.sup.2 (E. A. Lefrak et al., Cancer, 32:302, 1973). Even at or near the recommended maximum total cumulative dosage (430-650 mg/M.sup.2) significant and persistent heart dysfunction occurs in 60% of patients and 14% develop congestive heart failure (A. Dresdale et al., Cancer, 52:51, 1983). Thus, while these drugs are useful to inhibit the growth of cancerous tumors, the patient may die of congestive heart failure because of the severe cardiotoxic side effect of the drugs.
Some researchers believe that the cardiotoxicity is a result of free radical generation by the quinone moiety of the anthracycline molecule (J. Dorowshow et al., J. Clin. Invest., 68:1053, 1981; D. V. Unverferth et al., Cancer Treat. Rev., 9:149, 1982; J. Goodman et al., Biochem. Biophys. Res. Commun., 77:797, 1977; J. L. Zweier, J. Biol. Chem., 259:6056, 1984). On the other hand, there is good evidence that free radical generation may not be the only mechanism of cardiotoxicity because the drugs still produce cardiac damage in the presence of free radical scavengers (J. F. VanVleet et al., Am. J. Pathol., 99:13, 1980; D. V. Unverferth et al., Am. J. Cardiol., 56:157, 1985; C. Myers et al., Seminars in Oncology, 10:53, 1983; R. H. M. Julicher et al., J. Pharm. Pharmacol., 38:277, 1986; E.A. Porta et al., Res. Comm. Chem. Pathol Pharmacol., 41: 125, 1983).
It has also been found that inhibition of free radical generation does not eliminate the cardiotoxicity of these anthracyclines (P. S. Mushlin et al., Fed. Proc., 45:809, 1986). This research shows, instead, that the cardiotoxicity of doxorubicin and daunorubicin, as manifested by a reduction in myocardial contractility, is also dependent upon the metabolic reduction of the 13-keto moiety to a 13-dihydro metabolite. In test systems where doxorubicin is not metabolized appreciably to the 13-dihydro compound cardiotoxic effects are observed only at very high concentrations (200-400 micrograms/ml) (P. S. Mushlin et al., Fed. Proc., 44:1274, 1985; R. D. Olson et al., Fed. Proc., 45:809, 1986). In contrast, the 13-dihydro metabolites, doxorubicinol and daunorubicinol, produce cardiotoxicity in these same test systems at relatively low concentrations (1-2 micrograms/ml, R. D. Olson et al., Proceed. Am. Assoc. Cancer Res., 26:227, 1985; R. D. Olson et al., Proceed. Am. Assoc. Cancer Res., 28:441, 1987).
If doxorubicin is allowed to remain in the test systems even for short periods of time some metabolic conversion occurs and the 13-dihydro metabolite is formed in sufficient quantity so that cardiotoxicity begins to develop (L. Rossini et al., Arch. Toxicol. suppl., 9:474, 1986; M. Del Tocca et al., Pharmacol. Res. Commun., 17:1073, 1985). Substantial evidence has, thus, accumulated that the cardiotoxicity of drugs such as doxorubicin and daunorubicin results from the potent cardiotoxic effects produced by their 13-dihydro metabolites (P. Mushlin et al., Rational Drug Therapy, 22:1, 1988; S. Kuyper et al., FASEP Journal, 2:A1133, 1988; R. Boucek et al., J. Biol. Chem., 262:15851, 1987; and R. Olson et al., Proc. Natl. Acad. Sci., 85:3585, 1988).
The present invention makes use of the fact that the 13-deoxy forms of doxorubicin, daunorubicin, or other similar anthracyclines will not be metabolically converted to cardiotoxic 13-dihydro forms, and that the 5-keto group is modified to a form that will be less likely to generate free radicals, thus providing a means for administering compounds of the present invention in noncardiotoxic amounts without limitation of total cumulative dosage.